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Cited by 110Neuroinflammation and Neurodegeneration MechanismsParkinson's Disease Mechanisms and TreatmentsNuclear Receptors and Signaling

SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models

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Kwon, Oh‐Chan, Song, Jae‐Jin, Yang, Yunseon, Kim, Seong‐Hoon, Kim, Ji Young, Seok, Min‐Jong, Hwang, Inhwa, Yu, Je‐Wook +8 more·2021·EMBO Molecular Medicine
DOI 10.15252/emmm.202013076PMC PMC8033538
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Abstract

Astrocytes and microglia are brain‐resident glia that can establish harmful inflammatory environments in disease contexts and thereby contribute to the progression of neuronal loss in neurodegenerative disorders. Correcting the diseased properties of glia is therefore an appealing strategy for treating brain diseases. Previous studies have shown that serum/ glucocorticoid related kinase 1 (SGK1) is upregulated in the brains of patients with various neurodegenerative disorders, suggesting its involvement in the pathogenesis of those diseases. In this study, we show that inhibiting glial SGK1 corrects the pro‐inflammatory properties of glia by suppressing the intracellular NFκB‐, NLRP3‐inflammasome‐, and CGAS‐STING‐mediated inflammatory pathways. Furthermore, SGK1 inhibition potentiated glial activity to scavenge glutamate toxicity and prevented glial cell senescence and mitochondrial damage, which have recently been reported as critical pathologic features of and therapeutic targets in Parkinson disease (PD) and Alzheimer disease (AD). Along with those anti‐inflammatory/neurotrophic functions, silencing and pharmacological inhibition of SGK1 protected midbrain dopamine neurons from degeneration and cured pathologic synuclein alpha (SNCA) aggregation and PD‐associated behavioral deficits in multiple in vitro and in vivo PD models. Collectively, these findings suggest that SGK1 inhibition could be a useful strategy for treating PD and other neurodegenerative disorders that share the common pathology of glia‐mediated neuroinflammation.

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  • Pharmacological inhibition and silencing of SGK1 ameliorate pathological synuclein aggregation and PD-related behavioral deficits in various in vitro and in vivo MPTP-induced PD models, and protect midbrain dopaminergic neurons from degeneration.

    “Pharmacological inhibition and silencing of SGK1 can ameliorate pathological synuclein aggregation and PD-related behavioral deficits in various in vitro and in vivo MPTP-induced PD models. Moreover, this intervention protects midbrain dopaminergic neurons from degeneration”

    From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Kwon et al., 2021

    The Results report that SGK1 inhibition or silencing reduced synuclein pathology and protected midbrain dopamine neurons across PD models; inhibitor treatment also improved behavioral deficits in MPTP-treated mice. However, the Methods distinguish the MPTP mouse model from the synuclein-induced model, and the Results describe the aggregation experiments in synuclein-based models—not as various in vitro and in vivo MPTP-induced models. Page numbers are unavailable in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Beneficial effects of SGK1 inhibition may be related to enhancement of neuroglial activity, aiding clearance of glutamate toxicity and preventing neuroglial cell senescence and mitochondrial damage.

    “The beneficial effects of SGK1 inhibition may be related to its enhancement of neuroglial activity, which aids in the clearance of glutamate toxicity and prevents neuroglial cell senescence and mitochondrial damage”

    From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Kwon et al., 2021

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Cited by

Sorted by citations

Authors
Kwon, O., Song, J., Yang, Y., Kim, S., Kim, J. Y., Seok, M., Hwang, I., Yu, J., Karmacharya, J., Maeng, H., Kim, J., Jho, E., Ko, S. Y., Son, H., Chang, M., & Lee, S.
Affiliations
  • Hanyang University (KR)
  • University of Seoul (KR)
  • Yonsei University (KR)
  • Gachon University (KR)
Corresponding author
  • Chang, Mi‐Yoon
  • Lee, Sang‐Hun
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2021-03-01
Volume
13
Issue
4
Pages
e13076-e13076
ISSN
  • 1757-4676 (ISSN-L)
  • 1757-4684
DOI
10.15252/emmm.202013076
PMC
PMC8033538
OpenAlex
W3135551805
Cited by
110
References
22
Citations by year
2026: 17 · 2025: 24 · 2024: 21 · 2023: 23 · 2022: 16 · 2021: 9
FWCI
6.91
Type
journal article
Language
en
Update notices
correction (2025-08-11)
Open access
Licence
Locations
  • EMBO Molecular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
Funders
National Research Foundation of Korea (2017R1A5A2015395, 2017M3A9B4062415, 2020M3A9D80399925)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
Parkinson's disease, astrocytes, microglia, NF-κB signaling, NLRP3 inflammasome, cGAS-STING pathway, glutamate excitotoxicity, mitochondrial damage, dopaminergic neuron loss, alpha-synuclein aggregation, neurodegenerative diseases
MeSH terms
Animals, Disease Models, Animal, Glucocorticoids, Humans, Neuroglia, Parkinson Disease, Models, Animal, Dopaminergic Neurons

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